tbuckley/cabot-search huggingface dataset:
Adjuvant nivolumab plus ipilimumab vs placebo for patients with localized renal cell carcinoma at high risk of relapse after nephrectomy: Subgroup analyses from the phase 3 CheckMate 914 (part A) trial.
Authors: Robert J. Motzer, Paul Russo, Viktor Grünwald, Yoshihiko Tomita, Philippe Barthélémy, Jeffrey C. Goh, Hernán Javier Cutuli, Burcin Simsek, Julia Spiridigliozzi, Aleksander Chudnovsky, Axel Bex
Journal: Journal of Clinical Oncology (2023)

4506 Background: In part A of the CheckMate 914 trial, adjuvant nivolumab plus ipilimumab (NIVO+IPI) did not improve disease-free survival (DFS) vs placebo (PBO) in patients (pts) with localized renal cell carcinoma (RCC) at high risk of post-nephrectomy relapse (Motzer RJ, et al. Lancet 2023). Exploratory analyses were conducted to better understand outcomes in key pt subsets and with early NIVO+IPI discontinuation. Methods: Key study inclusion criteria were radical/partial nephrectomy with negative margins &gt; 4 and ≤ 12 weeks before randomization; predominant clear cell histology; pathological TNM stage T2a (grade [G] 3/4) N0M0, T2b-T4 (any G) N0M0, or any pT (any G) N1M0; and no evidence of residual disease/metastases. Pts in part A were randomized 1:1 to NIVO 240 mg Q2W (× 12) + IPI 1 mg/kg Q6W (× 4) or equivalent PBO for 24 weeks or until recurrence/unacceptable toxicity. Primary endpoint is DFS per blinded independent central review. Exploratory analyses assessed DFS by key subsets including Fuhrman grade, sarcomatoid features (yes/no), PD-L1 expression, and NIVO+IPI exposure (≤ 6 cycles [1–2 IPI doses] vs &gt; 6 cycles [3–4 IPI doses]). Safety was assessed by exposure. Results: 816 pts were randomized to adjuvant NIVO+IPI (N = 405) or PBO (N = 411). At 37.0 months median follow-up (min, 15.4 months), subset analyses suggested a DFS benefit for NIVO+IPI vs PBO in pts with Fuhrman grade 4 or sarcomatoid features. DFS by PD-L1 expression will be reported in the presentation. Pts who received &gt; 6 NIVO+IPI cycles trended toward improved DFS vs pts receiving ≤ 6 NIVO+IPI cycles. Of the 102 pts who received ≤ 6 NIVO+IPI cycles, 3% had sarcomatoid features, and 20% had Fuhrman grade 4; treatment discontinuation in these pts was due to study drug toxicity (75%), unrelated adverse events (AEs; 6%), pt request (5%), recurrence (4%), consent withdrawal/non-compliance (4%), or other (6%), and most pts receiving ≤ 6 NIVO+IPI cycles were discontinued without initial dose delay (NIVO, 84%; IPI, 89%). In the group of patients who received ≤ 6 NIVO+IPI cycles, grade 1–2 all-cause AEs were reported in 35% of pts (grade ≥ 3, 63%) and 31% of pts discontinued treatment due to grade 1–2 all-cause AEs (grade ≥ 3, 44%). Conclusions: Exploratory analyses suggest that tumor grade and sarcomatoid features influence outcomes with adjuvant NIVO+IPI. Limited NIVO+IPI exposure (≤ 6 cycles) and discontinuation for low-grade AEs may have contributed to the lack of DFS benefit observed in CheckMate 914 part A. Clinical trial information: NCT03138512 . [Table: see text]
Clinical efficacy and safety of regorafenib for patients with recurrent hepatocellular carcinoma after hepatectomy: A real-world study in China.
Authors: Yanbin Ni, Jiaxi Zheng, Yang Wang, Zhao Li, JiYe Zhu, Jie Gao
Journal: Journal of Clinical Oncology (2023)

e16119 Background: The therapeutic strategy for recurrent hepatocellular carcinoma (HCC) after hepatectomy is limited. There is a significantly unmet clinical need for effective treatment options for these patients. This study aimed to assess the clinical efficacy and safety of regorafenib alone or combined with a PD-1 inhibitor as a second or further-line treatment for patients with recurrent HCC after hepatectomy. Methods: Patients receiving regorafenib alone or combined with a PD-1 inhibitor in Peking University People’s Hospital from January 2019 to November 2022 were entered prospectively into a clinical database. Data were retrospectively analyzed. The major inclusion criteria were: histologically confirmed diagnosis of HCC; disease recurrence after radical hepatectomy; with tumor that cannot be re-resected; ECOG performance status score (PS) ≤2. Regorafenib was administered at the daily dose of 80-120 mg for more than 4 weeks. Progression-free survival (PFS) was the primary endpoint. The second outcomes included PFS, objective response rate (ORR), disease control rate (DCR), and the incidence of drug-related adverse events (AEs). CTCAE v5.0 was used for evaluation of AEs. Results: Twenty-two patients were enrolled with a median age of 59. The hepatic function of all patients was mildly impaired (Child-Pugh A). Among all patients, 36.35% of cases were enrolled in Barcelona Clinic Liver Clinic (BCLC) A and the remainder were in BCLC B. Eight cases (36.36%) received regorafenib in combination with PD-1 inhibitor therapy and 14 cases received regorafenib treatment alone. Among all patients, 86.36% of the cases were treated with regorafenib as second-line therapy. Five patients (22.73%) had extrahepatic metastasis. The median PFS and overall survival (OS) were 11.66 (±10.20) months and 16.92 (±10.21) months, respectively. The 3-month PFS rate was 100%. The 6-month and 12-month PFS rates were 75% (95%CI: 58.49%-96.70%) and 53.33% (95%CI: 34.88%-81.50%), respectively. The results showed a significant difference in median PFS between patients receiving regorafenib as second-line therapy and third-line therapy [12.30 months (95%CI: 4.25-20.36) vs 4.30 months (95%CI: 3.50-5.10); P&lt;0.001]. In addition, there is a significant difference in median PFS between patients with extrahepatic metastasis and those without extrahepatic metastasis [5.20 months (95%CI: 3.48-6.92) vs 18.20 months (95%CI: 5.09-31.31; P=0.003)]. The ORR and DCR were 18.18% and 81.82%. The most frequent AEs were hand-foot syndrome (40.91%), pain (18.18%), diarrhea (13.64%), and hypertension (13.64%). Most AEs were grade 1 or 2, with only 1 case having grade 3 AE. Conclusions: Regorafenib alone or combined with a PD-1 inhibitor showed significant clinical efficacy in controlling the disease progression of recurrent HCC.
Intravenous (IV) infusion of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, as monotherapy in advanced solid tumors: Preliminary results from an ongoing phase 1/2a study.
Authors: Jiaxin Niu, Minal A. Barve, Alexander I. Spira, William Jeffery Edenfield, Weijia Pang, Wenmin Fu, Yingxin Lu, Meredith McKean
Journal: Journal of Clinical Oncology (2023)

e14689 Background: Oncolytic virotherapy has emerged as a promising anticancer treatment. To date, almost all oncolytic viruses (OVs) are delivered via intratumoral (IT) injection, which limits its broad clinical application. Systemic delivery of OVs, a more practical option for patients (pts) without injectable lesions, allows both primary tumor and metastases treated simultaneously. However, due to concerns for immune clearance and the potential cytokine storms, very few studies thus far are conducted using OVs intravenously. T3011 is a genetically modified, next-generation oncolytic HSV-1 expressing IL-12 and PD-1 antibody. Extensive preclinical studies have demonstrated the feasibility, safety and efficacy of T3011 delivered intravenously. Here, we present preliminary results of IV T3011 as a single agent. Methods: In this phase 1/2a, multi-center, open label, dose escalation and expansion study, T3011 was administered intravenously on Days 1, 4, 8 of a 21-day cycle in pts with advanced solid tumors. The primary objective was to evaluate the safety and tolerability of escalating doses of IV T3011, characterize dose limiting toxicities (DLTs) and identify the MTD and RP2D of IV T3011. Phase 1 portion used a 3+3 design in 4 escalating cohorts (1×10 6 , 1×10 7 , 1×10 8 , 3×10 8 PFU). Pharmacokinetics, immunogenicities and pharmacodynamic profiles were studied in various samples. Results: As of Jan 2023, 10 pts received IV T3011 therapy: 4 in Cohort 1, 3 in Cohort 2, and 3 in Cohort 3. Median number of doses was 8. T3011 was well tolerated with no ≥ Grade 3 treatment-related adverse events (TRAEs) and no DLTs to date. Nausea and infusion-related reaction (including postdose delayed fever, chills, rigors, etc.) were the most common TRAEs. 7 of 10 pts had ≥ 1 tumor assessment, 4 achieved stable disease (SD) by RECIST 1.1 with a disease control rate of 57.1%, 2 had SD for ≥ 6 months. 1 pt had a postdose tumor biopsy revealing T cell activation via transcriptome profiling and gene ontology analysis. T3011 DNA was detected in blood in 9/10 pts at 0.5 hours after the 1 st dose and its level was dose-dependent and increased with repeated doses. T3011 DNA clearance was observed at 4-7 days after dosing. Saliva and urine samples from all pts were tested for T3011 DNA, only one was positive with very low DNA copies in a saliva sample at 0.5 h after the 2 nd dose from a pt in Cohort 1. Of note, pre-existing HSV-1 IgG had no impact on T3011 activity. Conclusions: IV T3011 monotherapy was well tolerated and safe at the first 3 dose levels, highly unlikely to be transmissible. Preliminary efficacy was encouraging. Our results also suggest T3011 IV treatment could stimulate anti-tumor immunity in the tumor microenvironment. Clinical trial information: NCT04780217 .
The insights of mutations of gynecological oncology by liquid biopsy for Chinese patients.
Authors: Yan Huang, Yan Yin, Bo Peng, Bo Hu, Shifu Chen, Meiqin Zhang
Journal: Journal of Clinical Oncology (2023)

e17501 Background: Liquid biopsy drew dramatic attention in the field of cancer research because of its attribution of nontraumatic, easy to obtain, providing overall state of tumor, allowing for real-time monitoring and so on. However, the transformation from research to application of liquid biopsy technique in clinical gynecological oncology management require more evidence and further investigation. Methods: Blood samples of 104 patients were collected, of whom 33 were diagnosed as cervical cancer, 20 were diagnosed as endometrial cancer, and 51 were diagnosed as ovarian cancer. cfDNA were extracted from blood and examined by next-generation sequencing technique with Haplox HapOnco panel. cfDNA mutations were analyzed and compared with genomic mutations in tumor tissues in publications. Results: In cfDNA, there were 120 genes mutated in cervical cancer patients, 150 genes mutated in endometrial cancer patients, and 58 genes mutated in ovarian cancer patients. Detecting by cfDNA, the average number of mutations was 6 (4.1 to 7.9, 95% CI) for each cervical cancer patient, 8.1 (2.1 to 14.1, 95% CI) for each endometrial cancer patient, and 5.1 (3.7 to 6.5, 95% CI) for each ovarian cancer patient. As the mutations in cfDNA compared with those in tumor tissues, the results revealed that there was no significant difference in mutation rate for 94.2% genes in blood and tumor tissues for cervical cancer patients, 93.3% for endometrial cancer patients, and 98.3% for ovarian cancer patients. Besides, there were no significant differences in microsatellite instability rates in blood and tumor tissues for cervical cancer patients and endometrial cancer patients. Conclusions: Most mutated genes in tumor tissues were detected in blood for gynecological oncology patients. The mutation rate for most genes and microsatellite instability rate had no significant difference in blood and tumor tissues, which suggested that liquid biopsy using cfDNA is helpful in gynecological oncology management.
RANO 2.0: Proposal for an update to the Response Assessment in Neuro-Oncology (RANO) criteria for high- and low-grade gliomas in adults.
Authors: Patrick Y. Wen, Martin J. Van Den Bent, Gilbert Youssef, Timothy Francis Cloughesy, Benjamin M. Ellingson, Michael Weller, Evanthia Galanis, Daniel Barboriak, John Frederick de Groot, Mark R. Gilbert, Raymond Yi-kun Huang, Andrew B. Lassman, Minesh P. Mehta, Annette Molinaro, Matthias Preusser, Lalitha Krishna Shankar, Wolfgang Wick, David A. Reardon, Michael A. Vogelbaum, Susan Marina Chang
Journal: Journal of Clinical Oncology (2023)

2017 Background: Response Assessment in Neuro-Oncology (RANO) criteria for high-grade and low-grade glioma (HGG and LGG) were developed to improve reliability of response assessment in glioma trials. Several limitations of the original RANO criteria have been reported. Methods: To address limitations of the original RANO criteria, a large cohort of patients with newly diagnosed and recurrent glioblastoma were evaluated comparing RANO-HGG with modified RANO (mRANO) and immunotherapy RANO (iRANO) criteria to inform the following proposed updates (RANO 2.0). Results: Based on the 2021 WHO classification of glioma, we recommend a single common set of criteria for all gliomas regardless of WHO grade and IDH mutational status. These criteria will be used for all trials regardless of the treatment modalities being evaluated. In newly diagnosed glioblastoma, the post-radiotherapy MRI, usually obtained approximately 4 weeks after completion of radiotherapy, rather than the post-surgical MRI as proposed in original RANO criteria, will be used as the baseline for comparison of subsequent scans. Since the incidence of pseudoprogression is high in the first 3 months following radiotherapy, confirmation of progression during this period with a repeat MRI (in 4-8 weeks) will be required for determining radiographic progression of disease (PD) if the patient is clinically stable. However, confirmation scans are not mandatory after this period nor for recurrent tumors since these scans do not appear to improve reliability in determining progression. For agents with a high likelihood of producing pseudoprogression such as viral therapies and some other immunotherapies, mandatory confirmation of progression with a repeat MRI is an option. The primary measurement will remain the 2-dimensional maximum cross-sectional area of tumor as the simplest method, but where resources are available, volumetric measurements are an option. For IDH wild-type tumors with contrast enhancement, non-enhancing tumor will no longer be evaluated with the possible exception of patients receiving antiangiogenic therapies. However, in tumors with a significant non-enhancing component, both the contrast enhancing and non-enhancing components will be evaluated as target lesions. Conclusions: We hope that these and other proposed changes by the RANO working group will improve response assessment in glioma clinical trials and help the development of more effective therapy for patients.
A single-center, prospective, single-arm, phase II trial to evaluate the adjuvant efficacy of camrelizumab with docetaxel plus S-1 for stage III (PD-L1<sup>+</sup>/dMMR/EBV<sup>+</sup>) gastric cancer after D2 resection.
Authors: Bo Ni, Xiang Xia, Yujing Guan, Linxi Yang, Linhua Ji, Enhao Zhao, Hui Cao, Gang Zhao, Chunchao Zhu, Zizhen Zhang
Journal: Journal of Clinical Oncology (2023)

e16089 Background: Immunotherapy has demonstrated promising efficacy and favorable safety profile for unresectable or metastatic gastric cancer (GC) by several high-quality studies. However, few have examined the immunotherapy efficacy for locally advanced GC (LAGC) in the perioperative setting, especially as adjuvant therapy after D2 resection. Here, a phase II trial reports the adjuvant efficacy of camrelizumab with docetaxel plus S-1 in patients (pts) with PD-L1 positive, deficient mismatch repair (dMMR) or Epstein-Barr virus (EBV) positive LAGC (NCT04152889). Methods: This is a single-center, prospective, open-label and single-arm phase II study. Chemotherapy-naive adult pts receiving D2 resection and histologically confirmed as PD-L1 positive (CPS &gt; 5), dMMR or EBV positive LAGC (stage III) were enrolled. Pts received camrelizumab (200mg, D1), docetaxel (40mg/m 2 , D1, free at first course) and S-1 (80-120mg, D1-14) every 3 weeks for seven courses, sequenced by camrelizumab (200mg, D1) and S-1 (80-120mg, D1-14) every 3 weeks for up to one year, until disease relapse or intolerable toxicity. Primary endpoint was 1-year relapse-free survival (RFS). Herein, the safety and efficacy data after 1-year postoperative therapy courses were reported. Results: From Jan. 2020 to Jan. 2022, 19 pts (median age 59 years, range 34-75, 13 men and 6 women) were enrolled, of whom 15 were CPS &gt; 5, 3 were dMMR, and 1 was EBV positive. pTNM stage IIIA, B and C were 10 (52.6%), 3 (15.8%) and 6 (31.6%), respectively. The cut-off date for the final follow-up data was Feb. 1, 2023 with a median follow-up period for surviving patients of 25.1 months. All 19 pts had experienced treatment related adverse events (TRAEs), of whom, grade 3-4 TRAEs occurred in 9 (47.4%), 2 pts (10.5%) discontinued therapy, and 11 pts (57.9%) delayed the therapy. Furthermore, the OS rate of 19 pts at 1/2 years was 100% and 88.9%, while the RFS rate at 1/2 years was 100% and 92.3%, respectively. The dead and recurrent cases all belonged to PD-L1 positive subgroup. Conclusions: Adjuvant therapy of camrelizumab with docetaxel plus S-1 shows acceptable safety and promising efficacy for PD-L1 positive, dMMR, or EBV positive stage III GC pts after D2 resection. Clinical trial information: NCT04152889 .
Effect of melanocortin-4 receptor antagonist TCMCB07 on chemotherapy-induced anorexia and weight loss in rats.
Authors: Xinxia Zhu, Eric J. Roeland, Mason A. Norgard, Kenneth Gruber, Russell Potterfield, Daniel Marks
Journal: Journal of Clinical Oncology (2023)

e15196 Background: We previously reported that peripheral administration of TCMCB07, a synthetic antagonist of the type 4 melanocortin receptor (MC4R), ameliorates cancer- and chronic kidney disease-associated cachexia in rats. In this study, we used a rat model of cisplatin and 5-FU to evaluate the efficacy of TCMCB07 in alleviating chemotherapy-induced anorexia, weight loss and muscle wasting. Methods: Two separate experiments were performed in a total of 58 rats. 1) Cisplatin (Cis)/TCMCB07 experiment with 3 groups: Cis/saline (n = 11), Cis/TCMCB07 (n = 11), Saline/saline (n = 6). 2) 5-FU/TCMCB07 experiment with 3 groups: 5-FU/saline (n = 12), 5-FU/TCMCB07 (n = 12), Saline/saline (n = 6). Rats were treated with Cis (2.5mg/kg), 5-FU (70 mg/kg), or saline via IP injection once weekly for 3 weeks. Rats were also treated with TCMCB07 (3 mg/kg/day) or saline via daily SC injection for 21 days. Food intake and body weight were measured daily. Body composition was analyzed pre- and post-treatment by MRI. Heart and gastrocnemius were dissected and weighed after euthanasia. Results: Total food intake over 21 days was significantly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0006) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0134), and decreased in Cis/saline vs Saline/saline group (p = 0.001), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/saline or 5-FU/TCMCB07 vs Saline/saline group. Body weight was robustly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0007) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0013), and decreased in Cis/saline vs Saline/saline group (p = 0.0001) and 5-FU/saline vs Saline/saline group (p = 0.0041), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/TCMCB07 vs Saline/saline group. Cardiac and skeletal muscle loss was markedly attenuated in Cis/TCMCB07 vs Cis/saline (cardiac: 3.12% vs -11.95%, p &lt; 0.0001; skeletal: -3.88% vs -9.02%, p = 0.0259). Cardiac muscle loss was significantly attenuated in 5-FU/TCMCB07 vs 5-FU/saline group (1.40% vs -6.09%, p = 0.0131) and skeletal muscle was modestly changed (-4.17% vs -7.24%, p = 0.1782). While Cis/saline and 5-FU/saline groups lost 91.33% and 52.61% of fat mass respectively compared to Saline/saline group, Cis/TCMCB07 and 5-FU/TCMCB07 groups gained 37.68% (p = 0.0002) and 70.19% (p &lt; 0.0001). Conclusions: This preclinical trial provides evidence supporting peripheral TCMCB07 antagonism of central melanocortin signaling, increasing food intake and anabolism, ultimately alleviating anorexia, weight loss and muscle wasting over multiple cycles of cisplatin or 5-FU chemotherapy.
Circulating exosomal PD-L1 to predict response with immunotherapy in patients with advanced cervical cancer.
Authors: Wenjie Tang, Qiufen Guo, Jinlong Chen, Qian Wu, Tingting Zhang, Qian Wang, Xueliang Zhang, Peng Xie
Journal: Journal of Clinical Oncology (2023)

e17514 Background: Programmed death ligand 1 (PD-L1) expression was wildly used to predict immune Check-Point Inhibitors (ICIs) efficiency. However, emerging results showed that PD-L1 was of great heterogeneity in sampling time and site. Recently, some studies found that exosomal PD-L1(ExoPD-L1) was related to ICIs response. In this study, we aimed to explore the predictive value of ExoPD-L1 in ICIs treatment of cervical cancer (CC) for the first time. Methods: 40 primarily diagnosed CC patients who accepted radical radiotherapy (RT) were included. The consecutive tumor sample were collected before and during RT. Another 37 advanced CC patients who accepted ICIs combination therapy were collected. Blood samples were collected from each participant before and during treatment. Exosomes were derived by differential centrifugation, which was further identified by Western blot (CD9/TSG101/Calnexin), transmission electron microscope analysis and nanoparticle tracking analysis. ExoPD-L1 detection was conducted by enzyme-linked immuno-sorbent assay (ELISA). The knockout of PD-L1 was conducted via CRISPR/Cas9 assay and the overexpress of PD-L1 was conducted by lentiviral transfection. CD8 + T cells were extracted from murine spleen by CD8 + T Cell Isolation Kit. Immune cells and cytokines markers were detected by multicolor flow cytometry. Results: The consecutive detection of PD-L1 showed a dynamic change during RT. Compared with the level before RT, PD-L1 expression elevated in most patients (87.5%, 35/40) after RT. And the responders (n = 18) had elevated ExoPD-L1 level at the first two circles in the ICIs combination therapy (P &lt; 0.001). Whereas the level of pre-treatment ExoPD-L1 couldn’t stratified clinical responders and non-responders (P = 0.181). The median follow-up time was 14.13 months. The mPFS in increased group vs. decreased group: not reach vs.11.02 months (P = 0.025, HR: 0.218, 0.052-0.913). Continuous blood sampling of mice models also found that effective therapeutic intervention could increase ExoPD-L1 in the early stage. The combination of exosome inhibitor GW4869 and anti-PD-1 further inhibited tumor growth. Mice were injected with external ExoPD-L1 OE and ExoPD-L1 KO . The results showed that ExoPD-L1 OE suppressed body immunity and promoted tumor growth. The results of flow cytometry showed that ExoPD-L1 OE inhibited CD8 + T cells from releasing interferon-γand granzyme B. And ExoPD-L1 OE also suppressed the CD8 + T cells proliferation in murine spleen. The coculture of CD8 + T cells and exosomes in vitro also confirmed the above conclusion. Conclusions: Compared with unstable and impressionable tumoral PD-L1, ExoPD-L1 seems to be better predictor for the efficacy of immunotherapy in CC, which was with easy accessibility and continuation. Exosome PD-L1 played an immunosuppressive role by inhibiting the proliferation and functional factor release of CD8+ T cell.